1. Field of the Invention
The invention relates generally to immunology and more specifically to methods for restoring dendritic cell (DC) homeostasis in a subject.
2. Background Information
The immune system is described as the tissues, cells, molecules and collection of biological processes involved in adaptive immunity, or the totality of host defense mechanisms responsible for such tasks as identifying and killing pathogens and tumor cells. One component of the mammalian immune system includes DCs which are immune cells whose primary function is to process antigen material and present it on the surface of the cell to other immune cells, thus functioning as antigen-presenting cells in mounting an immune response.
DCs control the balance between responding to antigens and immunological tolerance. Immature DCs continuously migrate through tissues and into lymphoid organs. Within secondary lymphoid tissue DCs can undergo limited proliferation, and their daughter cells retain the ability to present antigen to T cells. Once activated, they may interact with T cells and B cells to initiate and shape the adaptive immune response.
Several distinct subsets of DCs reside in secondary lymphoid organs, such as the spleen, that are distinguished by the cell surface markers, CD11c integrin and CD4 and CD8α co-receptors. Mouse splenic DC subsets include the CD8α+ DC subset, and the CD4+ and CD8α−/CD4− dual negative subsets, the latter two forming the CD8α− DC subset. These DC subsets acquire distinct antigen presenting functions, utilize different transcription factors, and require different trophic signals to control homeostasis.
Within secondary lymphoid organs, the lymphotoxin-β receptor (LTβR), a member of the TNF superfamily, selectively regulates the proliferation of CD8α− DC subsets. Splenic DCs undergo cell division, and the number of dividing CD8α− DCs is disproportionately reduced in the absence of the LTβR, although in normal bone marrow DC differentiation occurs in vitro. Of the two ligands for LTβR, LTαβ is the predominant ligand mediating steady state proliferation of CD8α− DC subsets in naïve mice, whereas both LIGHT and LTαβ can induce DC proliferation during inflammation. The CD8α− DC subset requires NIK and Rel B for proliferation in splenic tissues supporting a functional role of this LTβR pathway in vivo. A counter regulatory pathway for CD8α− DC subsets is mediated by the herpesvirus entry mediator (HVEM, TNFRSF14), a TNF receptor which also binds LIGHT and LTDα, and its non canonical coreceptor, B and T lymphocyte attenuator (BTLA).
The cellular interactions utilizing the signaling circuits formed by the LT-related signaling pathways are not well defined, due in part, from multiple hematopoietic lineages expressing membrane LTαβ, including naïve and activated T and B cells and NK cells. Naïve B cell expression of LTαβ promotes the post-natal maturation of lymphoid organs. A non-lymphocyte accessory cell population defined by CD4+IL7Rα+CD3−, referred to as the lymphoid tissue inducer (LTi) cells, express LTαβ during embryonic formation of secondary lymphoid organs and in the adult. These observations point to the conclusion that multiple lineages of cells may control the steady state proliferation of DC in lymphoid organs. Additionally, cytokines, including IL-2, IL-4 and IL-7, regulate expression of LTαβ in T cells and LTi cells, and cytokine signaling is necessary for lymphoid organogenesis, suggesting a link between cytokine signaling, LTαβ and DC proliferation.
Decreased numbers in the population of DCs, including specific DC subpopulations, have been associated with a host of immunodeficient states. Immunodeficiency is a state in which the host immune system's ability to fight infectious disease is compromised or absent. In various instances immunocompromised individuals are increasingly susceptible to developing diseases and disorders, such as infectious diseases and cancers. Immune deficiency may arise from genetic errors (e.g., primary immunodeficiencies), or may be acquired by infections by different pathogens, or caused by drugs that suppress the immune system (e.g., secondary or acquired immunodeficiencies).
A number of methods have been attempted to treat or complement immunodeficient individuals. For example, tissue or organ transplants have been performed in an attempt to treat certain genetic defects, such as bone marrow transfers. However, such attempts are limited by donor incompatibility and cellular tissue harboring the expressed defective gene. Further, defects in stromal cells may not be corrected by bone marrow transfer.
More daring attempts of transferring genes into hematopoietic stem cells using viral vectors have shown limited success, with poor transfer efficiency. Vectors have proven to be inherently unsafe with high incidence of inflammation following injection, or insertion into inappropriate sites in the genome, for instance when retrovirus vectors activate oncogenes causing cancer. Thus, there is a need to correct immunodeficiency by alternate mechanisms that are more efficacious, act on both lymphoid and non-lymphoid cells, and are safe. Specifically, an alternate safe approach is required to restoring homeostasis in patients with immunodeficiency by avoiding methods such as introducing vectors to transfer genetic deficiency, or requiring transfer into stem cells. Induction of DC proliferation and restoration of DC homeostasis via specific cell surface receptors present on DCs presents a useful strategy.